Rifaximin (INN; see The Merck Index, XIII ed., 8304) is a semi-synthetic non-aminoglycoside derived from rifamycin. More precisely, it is a pyrido-imidazo rifaximin, described and claimed in the Italian patent IT 1154655, whereas the European patent EP 0161534 describes a process for its production starting from rifamycin 0.
Rifaximin is (S-S, 16Z, 18E, 20S, 21S, 22R, 23R, 24R, 25S, 26S, 27S, 28E)-5, 6, 21, 23, 25-pentahydroxy-27-methoxy-2, 4, 11, 16, 20, 22, 24, 26-octamethyl-2,7-(epoxy pentadeca-[1,11,13] trienimino)-benzofuro [4,5-e]-pyrido[1,2-(alpha)]-benzimidazole-1,15(2H) dione, 25-acetate), and is represented in Formula 1.

Rifaximin is also currently sold under the trademark Normix®, Rifacol® and Xifaxan®.
Rifaximin is an antibiotic usually used for local action with a broad spectrum of action against Gram-positive and Gram-negative bacteria and aerobic and anaerobic organisms. Rifaximin has an excellent safety profile and it is characterized for a non-systemic absorption.
Rifaximin is used for the treatment of bowel infections caused by non-enteroinvasive bacteria, traveler's diarrhea, enteritis, dysentery, bowel inflammations such as, for instance, Crohn's disease (CD), ulcerous recto-colitis, irritable bowel syndromes (IBS), paucities, small intestinal bacterial overgrowth (SIBO), diverticular syndromes; pathologies directly or indirectly deriving from bowel infections, such as for instance hepatic encephalopathy, or which can be used in the pre- and post-operative prophylaxis of bowel infections.
U.S. Pat. No. 4,557,866 describes a process for the synthesis of pyrido-imidazo rifaximins comprising the reaction of rifamycin 0 with 4-methyl-2-aminopyridine.
EP 1557421B1, EP 1676847 B1, EP 1676848 B1 and U.S. Pat. No. 7,045,620 B2 describe polymorphic forms of rifaximin (INN), called rifaximin α, rifaximin β, and a poorly crystalline form called rifaximin γ. These forms can be obtained by hot-dissolving raw rifaximin in ethyl alcohol and by inducing subsequent crystallization of the product by addition of water at a given temperature and for a fixed time. The crystallization is then followed by a drying step carried out under controlled conditions, e.g., until a predefined water content is obtained, and the X-ray diffraction profile corresponds to one observed for one or more of the aforesaid rifaximin forms.
These patents also describe processes for the transformation from one polymorphic form to another, such as obtaining polymorph α by dehydration of polymorph β or polymorph γ; obtaining polymorph γ starting from polymorph α and the preparation of polymorph β by hydration of polymorph α.
U.S. Pat. No. 7,906,542 B2 describes pharmaceutical compositions comprising polymorphic forms of rifaximin α, β and γ.
EP 1682556 A2 describes polymorphic forms of rifaximin α, β and γ and their different in vivo absorption and dissolution profiles.
U.S. Pat. No. 7,915,275 B2 describes the use of pharmaceutical compositions comprising polymorphic forms of rifaximin α, β and γ for the treatment of bowel infections.
WO 2008/155728 describes a process for obtaining amorphous rifaximin by hot-dissolving raw rifaximin in absolute ethyl alcohol and then collecting after precipitation by cooling rifaximin under amorphous form.
Amorphous forms of rifaximin and processes for their obtainment are described in US 2009/312357 and US 2009/0082558, in particular US 2009/0082558 describes that amorphous rifaximin is obtained after precipitating by addition of water to a rifaximin solution in organic solvent.
WO 2009/108730 describes polymorphic forms of rifaximin (form ζ, form γ-1 (ζ), form α-dry, form η form ι, form β-1, form β-2, form ε-dry), salts, hydrates and amorphous rifaximin, their use in the preparation of pharmaceutical compositions and therapeutic methods related to their use.
WO 2011/153444 describes polymorphic forms of rifaximin κ and θ and WO 2011/156897 describes polymorphic forms of rifaximin called APO-1 and APO-2.
WO 2006/094662 describes polymorphic forms δ and ε of rifaximin useful in the preparation of pharmaceutical forms for oral and topical use. Said forms are obtained by means of processes comprising hot dissolution of raw rifaximin in ethyl alcohol, then addition of water at predetermined temperatures and for predetermined time periods, then drying under vacuum.
Viscomi et al., Cryst. Eng. Comm., 2008, 10, 1074-1081 describes the process for the preparation of polymorphic forms of rifaximin and their chemical, physical and biological characteristics.
Bacchi A. et al. New Journal of Chemistry (2008), 32; 10; 1725-1735, describe the preparation of crystals of tetra-hydrated rifaximin β with a water weight content corresponding to 8.4% (w/w), obtained by slowly evaporating water/ethanol solution of rifaximin at room temperature.
Rifaximin is a substantially water-insoluble molecule, and organic solvents are necessary to be added for increasing its solubility in aqueous solutions. Organic solvents are hardly acceptable in the preparation of substances for pharmaceutical use, and their use requires severe controls of the residual solvents in the final products.
Rifaximin water solubility can be varied within limited concentration ranges by selecting suitable polymorphic or amorphous forms. For example, WO 2005/044823 states that rifaximin polymorph α is substantially insoluble, whereas WO 2011/107970 states that an amorphous form of rifaximin obtained by means of spray-drying has a solubility of about 40 μg/ml after thirty minutes in aqueous solution, but this form is not stable and the solubility decrease over time and after two hours the solubility is about 9 μg/ml.
As described by Viscomi et al., Cryst. Eng. Comm., 2008, 10, 1074-1081, rifaximin solubility in suspension the presence of solid rifaximin may vary during the time according to possible transformation processes in more stable crystalline forms. In particular, it is described that also in case of substantially amorphous rifaximin polymorphs, solubility decreases in time until it coincides with the values obtainable with the more stable crystalline forms.
Rifaximin is also a local-action antibiotic, and the in-situ bioavailability of pharmaceutical compositions providing for increased available and local rifaximin concentrations (e.g., in physiological fluids such as gastric and intestinal fluids) is useful for treating all pathologies for which an increased rifaximin concentration can provide higher therapeutic efficacy.
There is a need in the art for rifaximin formulations having increased rifaximin solubility in aqueous solutions that provide increased rifaximin concentrations that are stable with time in comparison to those obtainable by the prior art.
There is also a need to provide rifaximin pharmaceutical compositions that include amino acids for the treatment of all the diseases wherein the amino acids are efficacious. There is also a need to provide the antibiotic effect of rifaximin with the effect of the amino for the treatment of hepatic disease and debilitated disease.
There is also a need to obtain compositions providing increased rifaximin concentrations at room temperature, that may be used directly in pharmaceutical preparations, in form such as tablets or clear solutions (replacing granulates in cloudy suspensions that are not well tolerated by patients) or in compositions for vaginal or rectal use. Preferably compositions having rifaximin concentrations higher than 3 μg/ml at room temperature would be obtained therefrom.
The provision of rifaximin solutions with increased rifaximin concentration are convenient for reducing the volumes of solution needed for use in industrial processes for preparing rifaximin compositions without the addition of large volumes of organic solvents.
In particular, rifaximin concentrations having increased solubility would be useful in formulating gastroresistant compositions promoting the release of high concentrations of rifaximin in the intestine for the treatment of bowel infections.
In the prior art, rifaximin can be obtained in powder, in raw form, in polymorphic or amorphous forms.
The information concerning the crystalline characteristics of rifaximin polymorphs available in the prior art has been obtained by means of the X-ray powder diffraction techniques. The obtained powder diffractograms are the result of the contribution of several micro-crystals (or crystallites) forming the powder; the observed powder diffraction signals which are often broadened and have a non-constant intensity, even re-analyzing the same sample, since the signals can be influenced by several factors, such as, for instance, the size and morphology of the crystallites and their distribution in the sample holder. Therefore, the univocal attribution to a settled phase of a water content as well as of an exact proportion of possibly present solvates and/or hydrates by means of X-ray powder diffraction can be rather difficult.
Generally, the crystal size and structure influences some properties of the powder of an active principle. For example, Kiang Y H et al., Int. J. Pharm., 368 (2009, 76) reports that mechanical properties, such as compressibility and flowability, are related to crystal morphology (structure) and that these properties influence the preparation of finished compositions in solid form.
Vippagunta S. R. et al., Adv. Drug. Del. Rev. 48 (2001), 3-26, discusses the relevance of controlling the crystalline (i.e., polymorphic) forms of an active principle during the various stages of its development, because each phase change due to interconversion of the polymorphs, to solvation processes, to hydrate formation and to change of crystallinity degree can alter the bioavailability of the drug.
The correlation between solid structure (i.e., morphology) and pharmacologically useful properties, such as bioavailability, is recognized as relevant information to be considered during the drug approval process. In fact, for giving their approval to the commercialization of drugs, health authorities require suitable analytical techniques for identifying the crystalline structure of the active principle, as well as production processes of the finished product for obtaining consistent amounts of the specific polymorphic forms. For example, the European Medicines Agency that regulates the granting of marketing authorization of drugs requires that the manufacturing methods of the active ingredients are standardized and controlled in such a way that they give homogeneous and sound results in terms of polymorphism of production batches (see, CPMP/QWP/96, 2003—Note for Guidance on Chemistry of new Active Substance; CPMP/ICH/367/96—Note for guidance specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances; Date for coming into operation: May 2000).
Therefore, the availability of sufficiently pure, high quality crystals of a particular polymorph or solvate (including hydrates) of a suitable size is critical and quite useful for providing analytical standards that enable the identification of single polymorphs present in mixtures.
The availability of the above described analytical standards is highly relevant to the pharmaceutical arts, for example, such analytical standards are useful for the identification of the polymorphic forms present, e.g., in a mixture, and for the identification of a particular species of solvate (e.g., hydrates) characterized by the stoichiometric ratio of water to active principle. It is well known that the presence or the absence of solvent molecules (e.g., water) in specific crystallographic positions can have an influence on the position of the peaks in a powder diffractogram and, in the case of rifaximin, knowing such positions would allow a better interpretation of these diffractograms.
Also, the availability of crystals suitable for analysis via single crystal X-ray diffraction enables the identification of individual polymorphs (and solvates thereof) in complex mixtures and also the exact water content of a polymorph could be determined thanks to the information provided by such technique. In particular, the quantitative characterization of a mixture including an amorphous form of the compound is difficult because the amorphous form does not give specific signals in a diffractogram, but instead is detectable by the presence of a raised baseline in the powder diffractogram. The availability of single crystal X-ray diffraction data as an analytical standard corresponding to the polymorphs and/or solvates present in the mixture, allows the quantification of the amount of amorphous substance in a mixture.
A better understanding of the crystalline structure is also relevant for the preparation of reproducible pharmaceutical compositions. For example, production processes can be modified in order to obtain compounds with reproducible crystallinity, thus guaranteeing the presence of properties corresponding to particular crystallinity related to particular polymorphic forms.